Trauma hemorrhagic shock-induced lung injury involves a gut-lymph-induced TLR4 pathway in mice.

Abstract

BACKGROUND:

Injurious non-microbial factors released from the stressed gut during shocked states contribute to the development of acute lung injury (ALI) and multiple organ dysfunction syndrome (MODS). Since Toll-like receptors (TLR) act as sensors of tissue injury as well as microbial invasion and TLR4 signaling occurs in both sepsis and noninfectious models of ischemia/reperfusion (I/R) injury, we hypothesized that factors in the intestinal mesenteric lymph after trauma hemorrhagic shock (T/HS) mediate gut-induced lung injury via TLR4 activation.

METHODS/PRINCIPAL FINDINGS:

The concept that factors in T/HS lymph exiting the gut recreates ALI is evidenced by our findings that the infusion of porcine lymph, collected from animals subjected to global T/HS injury, into naïve wildtype (WT) mice induced lung injury. Using C3H/HeJ mice that harbor a TLR4 mutation, we found that TLR4 activation was necessary for the development of T/HS porcine lymph-induced lung injury as determined by Evan's blue dye (EBD) lung permeability and myeloperoxidase (MPO) levels as well as the induction of the injurious pulmonary iNOS response. TRIF and Myd88 deficiency fully and partially attenuated T/HS lymph-induced increases in lung permeability respectively. Additional studies in TLR2 deficient mice showed that TLR2 activation was not involved in the pathology of T/HS lymph-induced lung injury. Lastly, the lymph samples were devoid of bacteria, endotoxin and bacterial DNA and passage of lymph through an endotoxin removal column did not abrogate the ability of T/HS lymph to cause lung injury in naïve mice.

CONCLUSIONS/SIGNIFICANCE:

Our findings suggest that non-microbial factors in the intestinal mesenteric lymph after T/HS are capable of recreating T/HS-induced lung injury via TLR4 activation.

• Authors: Diego C Reino, Vadim Pisarenko, David Palange, Danielle Doucet, Robert P Bonitz, Qi Lu, Iriana Colorado, Sharvil U Sheth, Benjamin Chandler, Kolenkode B Kannan, Madhuri Ramanathan, Da Zhong Xu, Edwin A Deitch, Rena Feinman
• Journal: PloS one (PLoS One) Vol. 6 Issue 8 Pg. e14829 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21829592 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• DNA Primers
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Nitric Oxide Synthase Type II

Topics

• Animals
• Base Sequence
• Blotting, Western
• DNA Primers
• Lung (enzymology)
• Lung Injury (etiology)
• Lymph Nodes (metabolism)
• Male
• Mice
• Nitric Oxide Synthase Type II (metabolism)
• Polymerase Chain Reaction
• Shock, Hemorrhagic (complications)
• Signal Transduction
• Swine
• Swine, Miniature
• Toll-Like Receptor 4 (metabolism)
• Wounds and Injuries (complications)